Amine hydriodides



Patented Aug. 30, 1933 2,128,741 M E HYDRIODIDES Frank B. Fisk,

Pitman-Moore Company,

corporation No Drawing. Application January 6, 1937,

' Serial No. 119,271

Indianapolis, Ind., assignor to PATENT OFFICE Indianapolis, Ind., a

6 Claims. (01. 167-40) This invention relates to iodine compoundssuitable for use in internal medication.

The chief object of this invention is to an iodine compound w produce,which is not which is stable to light and air.

The chief feature-of the invention consists in amine hydriodides in pureform.

The administration of iodine in internal medication is well known.Alkali salts of hydriodic acid, such as sodium and potassium iodide,have been commonly used for internal medication. The salts are solid andin order to obtain the desired internal medication efl'ect, largedosages are usually necessary. The material is usually given as tablets.The salts are objectionable because of their irritant action-on thestomach. With the large dosages usually necessary, the salts may causenausea and vomiting. In the absence of any better vehicle for supplyingiodine for internal medication, the medical profession perforce has beenrestricted thereto unless hydriodic acid has been used.

Hydriodic acid, it is well known, appears to give better medicationresults than these salts. However, due to the fact this acid will burnthe mucous tissues if administered, the same must be diluted. Thisrequires large dosages to secure the desired iodine medication effect.Usually when this liquid is used, it is administered as a syrup tominimize the burning efiect before mentioned.

There has been prepared the hydriodides of ethylene diamine. duced,to-wit, the dihydriodlde and the monohydriodide and either issatisfactory for the administration for internal medication purposes.Ei-

produce ther or both may be safely prepared. Either or both are readilysoluble each being a white crystal. Each is stable to light and air.Each contains an amount of iodine comparable to the amounts contained inthe alkali iodides. Each of these products when administered, does notcause nausea or vomiting, does not burnthe mucous tissues and may bereadily added to various pharmaceutical combinations for synergisticeffect in varying dosage. For example, either or both may be used incombination with alkaloids of the purine group, such as theobromine,with purine alkaloids and sedative drugs of the barbital type, such asphcno-barbital, with the salicylates, with or without vegetable drugs,or in combinations like the so-called mixed treatment formula forsyphilis in which the new hydriodide would be treated with mercuricbichloride to give the corresponding soluble complex mercuric iodide.

on is not dangerous to dangerous in its use and' Two forms have beenpro- The foregoing are set forth as examples of the use of either orboth of these products. A number of other such possible combinationswill readily suggest themselves to persons skilled in this art and suchcombinations are possible because these products contain iodine ininorganic combination and in amounts comparable to those found in thealkali salts and are readily soluble in water and other 'media.When-"administered directly in solution, their taste may be readilydisguised. Briefly stated, therefore, either or both of these compoundspossess all the desirable therapeutic features of hydriodic acid but arein solid form and avoid the administration of the free acid with itsattendant disadvantages, and they possess the desirable therapeuticfeatures of the alkali salts of hydriodic acid without the attendantirritant actionon the stomach or the accompanying nausea and vomiting.Likewise, comparable to alkali salts of hydriodic acid they are entirelystable to light and air.

The two salts have these formulas:-

While both salts are quite satisfactory, as previously stated, asmedicaments, the latter con- A convenient method of preparing thesesalts by way of illustration only, is by mixing suitable molecularquantities of the concentrated aqueous solutions of ethylene diamine andhydriodic acid commercially available. Reaction occurs immediately. Thedesired salts will be readily obtained by concentrating the mixture on awater bath until crystallization takes place. The crystals are thenfiltered, washed thoroughly and then dried. The product is then usuallypure enough for immediate use. If and when necessary, the

product can be further purified by recrystallization from varioussolvents. A mixture of ethyl alcohol and water is especially suitablefor this purpose.

-The quantities of the reagents to be used may be calculated from theirstrengths, if known. When their strengths are unknown, an indicator maybe used to determine when the mixture has 'R-EISSU ED reached the properdegree of acidity. If, for instance, the mixture is neutral tometacresol purple or bromphenol blue, the product obtained oncrystallization is the pure dihydriodide. If, however, the mixture isless acid, a mixture of the two salts, before mentioned, will beobtained, the proportion of monohydriodide increasing with decreasingacidity until finally when the acidity is suitable, the monohydriodideis obtained as pure crystals.

From the foregoing, therefore, it is evident that either salt may beobtained in pure form or any predetermined mixture of these salts may beobtained.

By way of illustration only, the following example of the preparation ofthe dihydriodide will now be given. To 45 lbs. of an aqueous solution ofhydriodic acid (about 62/5%) was added gradually with stirring, 9 lbs. 2oz. of an aqueous solution of ethylene diamine (about 70%). To thismixture was added the mother liquor from a previous similar lot.Titration of a sample of the mixture, using metacresol purple as anindicator, then showed 5 lbs. of hydriodic acid must be add- -ed torender the whole solution neutral to this indicator. When this amount ofacid was added to the mixture, the same was heated on the water bathuntil a crystal crust over the surface of the solution or a pellicle wasformed. The mixture was then cooled and allowed to crystallize. Thisresulted in the formation of relatively large size crystals. If themixture is stirred during the cooling, the size of the crystals will bematerially reduced. For tablet preparation, the latter procedure ispreferred. The crystals were then removed by filtration, washedthoroughly with alcohol and dried. Analysis of a sample of the crystalsshowed the iodine content thereof to be 80.1%. The theoreticallycalculated content is 80.37%.

It is, of course, to be understood that the details of preparation mayvary considerably without essentially altering the basic process. Forinstance, either or both of the reagents may be used in the pure state,since both are liquids, or they may be used in other than aqueoussolutionsthat is, in solutions which are not inimical to each other orto the resulting product or subsequent procedure.

Also, it is to be understood that concentration and crystallization maybe accomplished by other procedure than that specified. Such aconcentration and crystallization, for example, which is alternative incharacter, may be as by spraying the solution into a heated current ofair. Any num er of variations of the procedure hereinbefore specified byway of example, will readily suggest themselves to persons skilled inthis art.

In addition to the hydriodides of ethylene diamine, before mentioned,there has been prepared and studied the hydriodides of monoethanolamine,diethanolamine and triethanolamine. These resemble very closely thesalts of ethylene diamine in appearance, properties and method ofpreparation. Each of these bases is capable of forming one salt withhydriodic acid. Each of these salts is similarly efiective medically andpossesses the same advantages for iodine medication that the two firstmentioned salts possess. However, their iodine content is markedlylower.

Hence, a greater amount of these last mentioned salts must be used toprovide iodine dosage equivalent to a given amount of either of the twofirst mentioned salts. These several salts each have the general formula(CHzOHCHz) :NHc-n .HI

harmful physiological actions of some of the other amines might preventtheir use in particular instances. The selection of ethylene diamine,monoethanolamine, diethan'olamine and triethanolamine has beenintentional, solely because each of the same is less toxic than otherwell known readily available amines.

With reference to the salts initially mentioned hereinbefore, it may besaid that clinical results with a combination of theobromine,phenobarbital and ethylene diamine dihydriodide demonstrate that by theuse of this particular iodide, not only is satisfactory iodine action ormedication secured without stomach irritation but the effect thereof ismore prolonged than with the use of the ordinary alkali iodides so thatthe frequency and/or size of the doses (for example tablets) may bediminished.

While the invention has been described in great detail in the foregoingspecifications, the same is to be considered as illustrative and notrestrictive in character. Various modifications of the method ofpreparation of the compounds prepared will readily suggest themselves topersons skilled in this art and the same as well as the modificationshereinbefore mentioned specifically, are all considered to be within thebroad scope of the invention, reference being had to the appendedclaims.

The invention claimed is:--

1. An amine hydriodide derived from an amine selected from the groupconsisting of ethylene diamine and ethanolamines and suitable for theadministration of iodine in internal medication.

2. Ethylene diamine monohydriodide.

3. Ethylene diamine dihydriodide.

4. A mixture of ethylene diamine monohydrlodide and ethylene diaminedihydriodide.

5. A salt of hydriodic acid having the general formula(CH2OHCH2):NH(3z).HI where a: is an integer not greater than 3.

6.- A medicinal composition for the internal administration of iodineincluding an amine hydriodide selected from the group consisting ofethylene diamine and ethanolamine hydriodides.

FRANK B. FI SK.

